Asthma has long been a major medical problem throughout the world, especially in well-developed countries. To further compound the problem, both the incidence and severity of asthma appear to be on the increase. For example, during the period of 1980-1994, the reported incidence of asthma rose 75% in the United States. By 1998, 17 million Americans, 4.8 million of whom are children, were diagnosed with asthma. An estimated 5,000 asthma-related deaths occur each year in the United States. Centers for Disease Control and Prevention, Morbidity and Mortality Weekly Report 47, 1022-25; Focus on Asthma, National Institute of Allergy and Infections Disease.
Asthma is a disease in which bronchial constriction occurs resulting in impaired air flow followed by an infiltration of eosinophils and lymphocytes in the peribronchial tissues. Thus, an inflammatory process appears to be involved in the underlying reasons for allergic-based asthmatic reaction.
To date, no true in vivo antagonist of the vitamin D hormone has been disclosed. However, the following two compounds have been reported to act as vitamin D antagonists in vitro in the Schering laboratories. Herdick M., Steinmeyer A., and Carlberg, C. J. Biol. Chem., 275, 16506-16512 (2000); Herdick, M., Steinmeyer, A., and Carlberg, C. Proceedings of the 11th International Vitamin D Workshop, (Norman, A. W., Bouillon, R., Thomasset, M. eds.), pp. 259-262. Schaub, K., Steinmeyer, A., and Bunte, T. Proceedings of the Tenth Workshop on Vitamin D (A. W. Norman, R. Bouillon, and M. Thomasset, eds.), pp. 220-221 (1997).
Related compounds having a 2α-methyl group have also been disclosed. Fujishima, T., Kojima, Y., Azumaya, I., Kittaka, A., and Takayama, H. Bioorg. Med. Chem. 11, 3621-3631 (2003). The structures of the 2α-methyl compounds disclosed by Fujishima et al. are provided below
Because the six compounds depicted above are esters, delivery by circulation to target tissue may be limited unless they first undergo hydrolysis. However, these and other compounds, if delivered by inhalation, i.e. through an aerosol from an inhaler or nebulizer, may prove effective in blocking the asthma process. However, the activity of the above compounds is less than might be achieved with other more potent antagonists. Therefore, a need exists for new analogs with increased antagonistic potency which may additionally possess greater bioavailability and methods for administration.
In recent years, it has been discovered that removal of the 19-methylene group from the 10-carbon of the vitamin D molecule does not interfere with its activity in terms of binding to the receptor or in causing cellular differentiation. Perlman, K. L., Sicinski, R. R., Schnoes, H. K., and DeLuca, H. F. Tetrahedron Lett. 31, 1823-1824 (1990); Sicinski, R. R., Prahl, J. M., Smith, C. M., and DeLuca, H. F. J. Med. Chem. 41, 4662-4674 (1998). Furthermore, it has been discovered that substitution of either a methylene or an alkyl group on the 2-carbon markedly improves biopotency and selectivity of analogs over the vitamin D molecule. Based upon these observations and the need for vitamin D analogs with increased antagonistic potency and greater bioavailability, the ester compounds disclosed herein are synthesized for inhalation delivery and the ketone compounds disclosed herein are synthesized for both inhalation and systemic delivery.
The synthesis methodology described in Sicinski, R. R. et al., J. Med. Chem., 41, 4662 (1998), and that set forth in U.S. Pat. No. 5,843,928, which are both hereby incorporated by reference in their entireties and for all purposes as if fully set forth herein, are used to prepare these analogs using the procedures set forth herein. These analogs are soluble in propylene glycol solutions and can readily be made into an aerosol-delivery system for use with a nebulizer or an inhaler. These compounds will block asthma while avoiding the typical side effects associated with the steroids commonly used to treat asthma.
The active hormonal form of vitamin D, is 1α,25-dihydroxycholecalciferol (also referred to as calcitriol or 1α,25-dihydroxyvitamin D3). The structure of calcitriol is shown below and includes the numbering scheme of the carbon atoms used in such compounds and related analogs.
                1α,25-Dihydroxyvitamin D3=1,25-Dihydroxycholecalciferol=Calcitriol        
Recently, a new class of vitamin D analogs was discovered, the so-called 19-nor vitamin D compounds, which are characterized by the replacement of the A-ring exocyclic methylene group (carbon 19), typical of the vitamin D system, by two hydrogen atoms. Further substitution at the 2-position and/or modification of the side chain attached to carbon 17 of the five-membered ring has led to pharmacologically active compounds that are much less calcemic at physiologically active concentrations compared to the native hormone. Select analogs such as those disclosed herein exhibit antagonistic activity with respect to the vitamin D receptor and are effective for use in treating asthma and eczema. Various methods of synthesizing 19-nor-vitamin D analogs have been disclosed (see Perlman et al., Tetrahedron Lett. 31, 1823 (1990); Perlman et al., Tetrahedron Lett. 32, 7663 25(1991), and DeLuca et al., U.S. Pat. No. 5,086,191). The synthesis of various intermediates for use in the preparation of various 19-nor vitamin D analogs is disclosed in U.S. Pat. No. 5,086,191 which is hereby incorporated by reference in its entirety and for all purposes as if fully set forth herein.